Breast cancer is responsible for the second overall cause of cancer-related deaths among women. Despite this profound health risk, Immunotherapy for breast cancer has not been adequately developed as an integral part of the adjuvant therapy setting. Tumor specific antigens have long provided less than optimal results as targets for cancer vaccination. Although current advances show renewed promise using tumor specific targeted strategies, other recent studies indicate that normally expressed differentiation autoantigens may be both effective and acceptable targets for cancer vaccination particularly if any resultant autoimmune consequences are tolerable. Such conditions are evident in breast cancer since the affected organs are typically removed or ablated as part of therapy, and their removal, though traumatic, is not life-threatening. Thus, our overall hypothesis here is that a full-strength autoimmune attack sufficient to induce targeted breast-specific failure will provide protection and therapy against breast malignancies. In our preliminary studies, we have characterized the first autoimmune-induced animal model for breast failure. We found that immunization of mice with the breast-specific differentiation antigen, a-lactalbumin, results in profound breast failure characterized clinically by severe lactation insufficiency and a failure-to-thrive nourishment deficiency in pup offspring. In addition, we found that immunization with a-lactalbumin provides both protection against the spontaneous development of autochthonous tumors in transgenic mice as well as therapy against growing inoculated murine breast tumors. Moreover, since a-lactalbumin is expressed in the majority of human breast cancers and since vaccination fails to induce any detectable autoimmune-mediated breast inflammation in non-lactating females, immunization with this breast-specific autoantigen may have clinical viability as a potent and effective preventive breast vaccine strategy for women in their post child-bearing years when lactation may be avoided. Thus, we provide evidence indicating that autoimmune targeted breast failure serves as an effective and viable strategy for preventive and therapeutic cancer vaccination. Our aims in the current proposal are designed to further evaluate the full potential of a-lactalbumin vaccination in providing breast tumor immunity. PUBLIC HEALTH RELEVANCE: We have developed and characterized the first animal model for autoimmune induced breast failure by immunizing mice with a-lactalbumin, a breast specific protein found in normal breast tissue and in the majority of human breast cancers. We have found that vaccination with a-lactalbumin protects mice from developing breast tumors and inhibits growth of established breast tumors. Our proposed experiments are designed to further evaluate the full potential of a-lactalbumin vaccination in providing immunity against breast cancer.